TY - JOUR
T1 - Visceral adipose tissue-derived serine proteinase inhibitor inhibits apoptosis of endothelial cells as a ligand for the cell-surface GRP78/voltage-dependent anion channel complex
AU - Nakatsuka, Atsuko
AU - Wada, Jun
AU - Iseda, Izumi
AU - Teshigawara, Sanae
AU - Higashio, Kanji
AU - Murakami, Kazutoshi
AU - Kanzaki, Motoko
AU - Inoue, Kentaro
AU - Terami, Takahiro
AU - Katayama, Akihiro
AU - Hida, Kazuyuki
AU - Eguchi, Jun
AU - Ogawa, Daisuke
AU - Matsuki, Yasushi
AU - Hiramatsu, Ryuji
AU - Yagita, Hideo
AU - Kakuta, Shigeru
AU - Iwakura, Yoichiro
AU - Makino, Hirofumi
PY - 2013/3/1
Y1 - 2013/3/1
N2 - RATIONALE:: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats. OBJECTIVE:: The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu. METHODS AND RESULTS:: Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arteries in diabetic Wistar rats. The expression of Ccl2, Pdgfb, and Pdgfrb genes was significantly reduced by the treatment of Vaspin-Ad. In cuff-injured femoral arteries, the intimal proliferation was ameliorated in vaspin transgenic (Vaspin Tg) mice. The application of recombinant vaspin and Vaspin-Ad promoted the proliferation and inhibited the apoptosis of human aortic endothelial cells. Adenovirus expressing vaspin with calmodulin and streptavidin-binding peptides was applied to human aortic endothelial cells, subjected to tandem tag purification and liquid chromatography-Tandem mass spectrometry, and we identified GRP78 (78-kDa glucose-regulated protein) as an interacting molecule. The complex formation of vaspin, GRP78, and voltage-dependent anion channel on the plasma membrane was confirmed by the immunoprecipitation studies using aortas of Vaspin Tg mice. The binding assay using I-vaspin in human aortic endothelial cells revealed high-affinity binding (dissociation constant = 0.565×10 m) by the treatment of 5 μM thapsigargin, which recruited GRP78 from the endoplasmic reticulum to plasma membrane by inducing endoplasmic reticulum stress. In human aortic endothelial cells, vaspin induced phosphorylation of Akt and inhibited the kringle 5-induced Ca influx and subsequent apoptosis. CONCLUSIONS:: Vaspin is a novel ligand for the cell-surface GRP78/voltage-dependent anion channel complex in endothelial cells and promotes proliferation, inhibits apoptosis, and protects vascular injuries in diabetes mellitus.
AB - RATIONALE:: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats. OBJECTIVE:: The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu. METHODS AND RESULTS:: Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arteries in diabetic Wistar rats. The expression of Ccl2, Pdgfb, and Pdgfrb genes was significantly reduced by the treatment of Vaspin-Ad. In cuff-injured femoral arteries, the intimal proliferation was ameliorated in vaspin transgenic (Vaspin Tg) mice. The application of recombinant vaspin and Vaspin-Ad promoted the proliferation and inhibited the apoptosis of human aortic endothelial cells. Adenovirus expressing vaspin with calmodulin and streptavidin-binding peptides was applied to human aortic endothelial cells, subjected to tandem tag purification and liquid chromatography-Tandem mass spectrometry, and we identified GRP78 (78-kDa glucose-regulated protein) as an interacting molecule. The complex formation of vaspin, GRP78, and voltage-dependent anion channel on the plasma membrane was confirmed by the immunoprecipitation studies using aortas of Vaspin Tg mice. The binding assay using I-vaspin in human aortic endothelial cells revealed high-affinity binding (dissociation constant = 0.565×10 m) by the treatment of 5 μM thapsigargin, which recruited GRP78 from the endoplasmic reticulum to plasma membrane by inducing endoplasmic reticulum stress. In human aortic endothelial cells, vaspin induced phosphorylation of Akt and inhibited the kringle 5-induced Ca influx and subsequent apoptosis. CONCLUSIONS:: Vaspin is a novel ligand for the cell-surface GRP78/voltage-dependent anion channel complex in endothelial cells and promotes proliferation, inhibits apoptosis, and protects vascular injuries in diabetes mellitus.
KW - apoptosis
KW - atherosclerosis
KW - diabetes mellitus
KW - endothelium
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U2 - 10.1161/CIRCRESAHA.111.300049
DO - 10.1161/CIRCRESAHA.111.300049
M3 - Article
C2 - 23307819
AN - SCOPUS:84874771915
VL - 112
SP - 771
EP - 780
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 5
ER -